I like to call 4-HO-DET "The Living Rainbow Crystal". I had the fortunate experience of aquiring 1.5 grams of this material before it was swept off the face of the earth by the DEA's Operation Web Tryp. I experimented a lot with it. Some of my experiences included: out of body experiences, merging of conciousness, connectedness to everything, multidimensional awareness, and pretty colors.
4-HO-DET is a synthetic analouge of psilocin (4-HO-DMT). It was first synthesized by Albert Hoffman, the discoverer of LSD. After inventing LSD Hoffman extracted psilocin, psilocybin, and baeocystine from psilocybe cubensis and started tweaking the psilocin molecule to see what he could come up with. The 4 position on the benzene ring of DET (diethyltryptamine) is hydroxylated. This is some magical stuff. The fact that it has an amino diethyl group is interesting because at the "top" of the LSD molecule there is also a diethyl group comming off of a nitrogen atom (albeit, an amide group). This is somewhat more difficult to synthesize than DET, its non-4-hydroxylated cousin. The use of diethyl ether, LAH, and THF makes it kind of dangerous for an ameture chemist to be messing with and 4-hydroxyindole is getting expensive. DET starts from tryptamine, which is inexpensive and pretty easy to find in sizeable quantities.
The indolol 4-HO-DET does not need to be salted out of solution as a HCl salt, it sets up as fine white crystals all by itself. This is because it is something of an internal salt. The lone pair of electrons on the amine are on one side of the molecule, the slightly positively-charged hydroxyl group is on the other side.
N,N-DIETHYL-4-HYDROXY; 4-INDOLOL, 3-[2-(DIETHYLAMINO)ETHYL];
N,N-DIETHYL-4-HYDROXYTRYPTAMINE; 3-[2-(DIETHYLAMINO)ETHYL]-4-INDOLOL; CZ-74;
4-HO-DET PHOSPHATE ESTER; TRYPTAMINE, N,N-DIETHYL-4-PHOSPHORYLOXY; 4-INDOLOL,
3-[2-(DIETHYLAMINO)ETHYL], PHOSPHATE ESTER;
PHOSPHATE ESTER; CEY-19
SYNTHESIS : To a
solution of 5.0 g 4-hydroxyindole in 20 mL pyridine there was added 10 mL acetic
anhydride and the reaction heated on the steam bath for 10 min. The reaction was
quenched by pouring over chipped ice to which was added an excess of NaHCO3.
After being stirred for 0.5 h the product was extracted with ethyl acetate and
the extracts washed with brine and the solvent removed under vacuum. The residue
weighed 6.3 g (95%) which, after crystallization from cyclohexane, had a melting
point of 98-100 °C. IR (in cm-1): 1750 for the carbonyl absorbtion.
To a solution of 0.50 g 4-acetoxyindole in 4 mL Et2O, that was stirred and
cooled with an external ice bath, there was added, dropwise, a solution of 0.5
mL oxalyl chloride in 3 mL anhydrous Et2O. Stirring was continued for 0.5 h and
the intermediate indoleglyoxylchloride separated as a yellow crystalline solid
but it was not isolated. There was then added, dropwise, a 40% solution of
diethylamine in Et2O until the pH was raised to 8-9. The reaction was then
quenched by the addition of 100 mL CHCl3, and the organic phase was washed with
30 mL of 5% NaHSO4 solution, with 30 mL of saturated NaHCO3, and finally with 30
mL of saturated brine. After drying with anhydrous MgSO4, the solvent was
removed under vacuum. The residue set up as crystals and, after
recrystallization from Et2O, provided 0.62 g (72%)
4-acetoxyindol-3-yl-N,N-diethylglyoxylamide with a mp of 150-151 °C.
A suspension of 0.5 g LAH in 10 mL anhydrous THF was held in an inert
atmosphere and vigorously stirred. To this there was added, dropwise, a solution
of 0.6 g of 4-acetoxyindol-3-yl-N,N-diethylglyoxylamide in 10 mL anhydrous THF
at a rate that maintained a gentle reflux. After the addition was complete, the
refluxing was maintained for an additional 15 min, cooled to 40 °C, and the
excess hydride killed by the addition of 1.0 mL EtOAc, followed by 2.3 mL H2O.
The reaction mixture was filtered free of solids under a N2 atmosphere, washed
with THF, and the filtrate and washings combined and stripped of solvent under
vacuum. The residue was distilled in a KugelRohr apparatus and the solid
distillate recrystallized from EtOAc/hexane to give 0.24 g (52%)
3-[2-(diethylamino)ethyl]-4-indolol (4-HO-DET) as white crystals with a mp of
103-104 °C. The product discolored quickly in the presence of air, and was best
stored under an inert atmosphere at -30 °C. Conversion to the phosphate ester
was achieved by reaction of the sodium salt of
3-[2-(diethylamino)ethyl]-4-indolol with dibenzylchlorophosphonate, followed by
the reductive removal of the benzyl groups with catalytic hydrogenation, as
described for psilocybin.
DOSAGE : 10 - 25 mg, orally (as the indolol, the acetate or the
DURATION : 4 - 6 hrs
QUALITATIVE COMMENTS : (with 15 mg indolol, orally) "This was in a
gelatin capsule and it came on from a half hour to the three-quarter hour point
like gang-busters. Time really slowed down, with sparkly-ness, interesting, and
yet there was a touch of sadness. The intense visuals held the scene, and there
was the compulsion to talk and to interact and to share stuff, but the erotic
was not to be found. I slept OK but there was something uncomfortable at a deep
level. Am OK."
(with 15 mg phosphate ester, orally) "It is meaningful to say that I ceased
to exist, becoming immersed in the ground of Being, in Brahman, in God, in
'nothingness,' in Ultimate Reality, or in some similar religious symbol for
oneness. The feelings I experienced could best be described as cosmic
tenderness, infinite love, penetrating peace, eternal blessing and unconditional
acceptance on one hand and, on the other, as unspeakable awe, overflowing joy,
primeval humility, inexpressible gratitude and boundless devotion. Yet, all of
these words are hopelessly inadequate and can do little more than meekly point
toward the genuine, inexpressible feelings actually experienced. It is
misleading even to use the words, 'I experienced,' as during the peak of the
experience (which must have lasted at least an hour) there was no duality
between myself and what I experienced. Rather, I was these feelings, or ceased
to be in them and felt no loss at the cessation. Four days after the experience
itself, I continue to feel a deep sense of awe and reverence, and am
simultaneously intoxicated with an ecstatic joy. This euphoric feeling is in no
sense analogous to hebephrenic giddiness; it includes elements of profound peace
and steadfastness, surging like a spring from a depth of my being which has
rarely, if ever, been tapped prior to the drug experience."
(with 20 mg orally indolol) "I felt this faster than psilocin, but being
twenty mg this is probably less potent."
(with 20 mg acetate ester, orally) "A mild stomach discomfort for twenty
minutes, followed by intoxication to the 40 minute point. A strange mixture of
things at an hour, sedation, jaw-tightening, and a generalized body tremor. The
light from the fireplace gave me bursts of color. Music allowed me to drift with
my thoughts. Anorexia was intense, in fact there was some gut disturbance
throughout the day, plus a lot of diuretic effect. Four hours into it I was fine
on the telephone to a friend who knew nothing about the day."
(with 25 mg acetate ester, orally) "There was nausea and motor incoordination
going into this. And my blood pressure went up a bit. The mental part of it all
peaked at 90 minutes and all closed-eye effects had stopped after three hours.
Another couple of hours and the body seemed to be OK again. Sleep OK, too. I am
not impressed with this stuff."
EXTENSIONS AND COMMENTARY : On the topic of psilocybin and psilocin,
one of the most frequent questions I am asked is, "Isn't it true that psilocybin
is immediately converted to psilocin in the blood stream, and so the two
chemicals are in essence identical, molecule for molecule?" At this moment I
always suppress a brief sense of mental fragmentation, with the automatic reply,
"Where is the evidence that psilocybin is converted to psilocin in man?" If it
exists, I certainly do not know of it. This clears my conscience. I really do
not know the answer. But I have a tremendously strong suspicion that it really
does. Any such ester, be it the phosphate, the sulfate, or the acetate, would
all be easily split to the archetypal indolol by the ubiquitous esterases in the
body. I do indeed believe, in my inner heart, that they all act upon the brain
as the same end product, psilocin. And here, with the N,N-diethyl homologue, the
same arguments probably hold as well.
The ratios of molecular weights for these ethyl homologues,
314 for the phosphate (CEY-19), the same for the sulfate (by the way, it's not
yet explored in man, to my knowledge), 276 for the acetate and 234 for the free
phenol (CZ-74), all fall into a pretty narrow range, from about 4 to 3. So, the
weight of the ester component in the actual molecule being considered is a
relatively minor factor in the dose calculation. I am at peace with the
hypothesis that all four compounds are interchangeable in potency.
Some fascinating studies have been done in Germany where the
metabolically active mycelium of some Psilocybe species have been administered
diethyltryptamine as a potential diet component. Normally, this mushroom species
dutifully converts N,N-dimethyltryptamine (DMT) to psilocin, by introducing a
4-hydroxyl group into the molecule by something that is probably called an
indole 4-hydroxylase by the biochemists. You put DMT in, and you get
4-hydroxy-DMT out, and this is psilocin. Maybe if you put Mickey Mouse in, you
would get 4-hydroxy-Mickey Mouse out. It is as if the mushroom psyche didn't
really care what it was working with, it was simply compelled to do its sacred
duty to 4-hydroxylate any tryptamine it came across. It was observed that if you
put N,N-diethyltryptamine (DET, not a material found in nature) into the growing
process, the dutiful and ignorant enzymes would hydroxylate it to
4-hydroxy-N,N-diethyltryptamine (4-HO-DET) a potent drug also not known in
nature. This is the title drug of this commentary. What a beautiful burr to
thrust into the natural versus synthetic controversy. If a plant (a mushroom
mycelium in this case) is given a man-made chemical, and this plant converts it,
using its natural capabilities, into a product that had never before been known
in nature, is that product natural? What is natural? This is the stuff of many
long and pointless essays.
A valuable concept was championed by one of the most respected
psychotherapists and academicians in recent years, Hanscarl Leuner, the Chairman
of the Psychotherapeutic Department of the University of Göttingen. Leuner was
convinced that the value of the psychedelic drug was in the opening of the
psyche with repeated modest exposures, with therapy carried forth over a period
of time. This is the "psycholytic" approach to therapy. An opposite approach is
called "psychedelic." Here there is what might well be a one-time interaction,
in which the patient is blasted into orbit with the hopes of his confronting his
problem and also finding its solution. When LSD is used in the former approach,
in psycholytic dosages, one would expect levels of between 50 and 150 micrograms
to be used; in the latter (psychedelic) approach, the dosage would be in the 500
to 1500 microgram range. The first calls upon the activation and development of
a process of understanding; the second can be seen as a religious crisis, or a
conversion event. In Europe, the first was favored, but there were strong
advocates (Unger, Pahnke, Grof) in the United States favoring the latter
process. Here, CZ-74 was thought to be suitable only in the psycholytic role, in
that it was too short lived and, at high doses, there was a restlessness and
body disturbance that was not usually seen with LSD.
There is a second instructive point to be learned from Leuner. It was he who
had made early observations of the psychological effects of CZ-74 in man (within
two years of the reported synthesis in about 1959) and had carried out the most
extensive clinical studies ever conducted, involving at least 160 trials in
human volunteers. He presented two separate reports in 1965, to two very
different audiences. To the psychotherapeutic audience there was a strong
emphasis made of the psycholytic virtues to be found in CZ-74, including its
very short duration and the positive nature of the experience. The sessions are
called "overwhelming and ecstatic" with the "elimination of the hangover of LSD
-- or any pathological after-effects -- even with dosages of up to 40
milligrams." The plaudits continued: "Thus, this drug must be considered to be
particularly safe and suited for ambulant psycholytic treatment and use by
psychiatrists in their practices." Almost everything was positive.
However, in addressing a neurosciences conference, also in 1965, and
referring to the same studies and the same experimental population, he reported
some pretty heavy duty neuropharmacological negatives. "In all sessions there
were disturbance of body image, illusions, pseudo-hallucinations and
hallucinations. In 50% of the cases, motor restlessness, aphasia, loss of
concentration and temporal and spacial disorientation could be clearly observed.
In 25% of the cases there was loss of impetus, derealization and acoustic
hallucinations. More rarely and only with the highest doses did extreme
psychotic symptoms occur, with increased volubility, depersonalization,
cosmic-mystic experiences, delirium, schizophrenic behavior with catatonic fits
and temporary paranoia." Almost everything was negative.
At a banquet associated with an international conference on the study of
consciousness, held in Göttingen a few years ago, Alice and I had the pleasure
of sitting at the table with Hanscarl Leuner and his wife. He thanked me for
inventing 2C-D which he and his students had been exploring as an adjunct to
psychotherapy. They had renamed it, initially DMM-PEA and then LE-25, and had
apparently explored it at dosages that reached into the hundreds of milligrams.
In PIHKAL, I had offered an effective range for this drug of from 20 to 60
milligrams. It would seem that in his later years, Dr. Leuner chose to move from
the psycholytic camp over to the psychedelic camp.
One final comment. When you read a paper or listen to a lecture offered by a
researcher of impeccable qualifications, take a moment to look about you to see
who is along side you in the audience that is being addressed. Who else is
reading his paper? Who else is hearing his lecture? How might the presentation
be tailored to fit the interests of the recipients? The identification and
recognition of your neighbors should play a role in your evaluation and
acceptance of the presentation.
The first half of the book is kept under strict copyright, however part 2 has been officially released for non-commercial use by the authors under the conditions described below. Each compound from part two will be separately hardlinked and noded. Unlike the hardlinks in the PiHKAL node, I have chosen to hardlink the common abbreviation or common name rather than the long chemical name. I believe this is friendlier to E2 noders and the search box. I mean, honestly, who is going to look for melatonin under n-acetyl-5-methoxy-tryptamine?
The Copyright for Part 1 of TiHKAL has been reserved in all forms and it may not be distributed. Part 2 of TiHKAL may be distributed for non-commercial reproduction provided that this notice, the cautionary notice and the ordering information are retained.
Cautionary Note - Please read before proceeding
I would like to take a moment to reiterate that at the present time restrictive laws are in force in the United States and it is very difficult for researchers to abide by the regulations which govern efforts to obtain legal approval to do work with these compounds in human beings..... No one who is lacking legal authorization should attempt the synthesis of any of the compounds described in these files, with the intent to give them to man. To do so is to risk legal action which might lead to the tragic ruination of a life. It should also be noted that any person anywhere who experiments on himself, or on another human being, with any of the drugs described herein, without being familiar with that drug's action and aware of the physical and/or mental disturbance or harm it might cause, is acting irresponsibly and immorally, whether or not he is doing so within the bounds of the law.
If you are seriously interested in the chemistry contained in these files, you can order the books TIHKAL: The Continuation, and PIHKAL: A Chemical Love Story by Ann and Alexander Shulgin. These books are available from:
P.O. Box 13675
Berkeley, CA 94712
Call or write to get ordering information.